WDR20a Inhibitors

Chemical inhibitors of WDR20a function predominantly by disrupting the cellular processes that WDR20a facilitates, rather than directly inhibiting the protein itself. These chemicals exert their effects by impeding the degradation pathway of ubiquitinated proteins, which WDR20a is known to be involved with. Bafilomycin A1, for instance, disrupts the optimal acidic environment required for the deubiquitination activity of WDR20a by inhibiting the V-ATPase proton pump, leading to an increase in lysosomal pH. This alteration in pH can attenuate the deubiquitination process in which WDR20a participates. Similarly, the chemicals MG132, Lactacystin, ALLN, Epoxomicin, Clasto-lactacystin β-lactone, Velcade (Bortezomib), Carfilzomib, Oprozomib, Ixazomib, and Delanzomib target the proteasome, a complex responsible for the degradation of polyubiquitinated proteins.

The inhibition of the proteasome by these chemicals leads to an accumulation of polyubiquitinated proteins within cells. As a protein involved in the deubiquitination process, WDR20a would be indirectly inhibited due to the oversaturation of substrates needing deubiquitination. The proteasome inhibitors, by preventing the breakdown of these proteins, create a bottleneck effect where the ubiquitin-proteasome system becomes overwhelmed. This results in an indirect inhibition of WDR20a, as it can no longer efficiently perform its role in the deubiquitination of proteins. Chemicals like MG132 and Lactacystin bind reversibly and irreversibly, respectively, to the proteasome, while others like Velcade, Carfilzomib, and Ixazomib are more selective in their inhibition of the proteasome's catalytic activity. Regardless of their mode of action, all contribute to the accumulation of ubiquitinated proteins, thereby limiting WDR20a's ability to mediate its normal deubiquitination functions.